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Background: There is a considerable association between major depressive disorder (MDD) and cardiovascular disease, most possibly relying on abnormalities in the autonomic nervous system (ANS)-related cardiac reactivity, although the exact underlying pathophysiological pathway is unclear. This study tends to shed some additional light on this background by investigating ANS reactivity in MDD with respect to previous depression history through an objective stress challenge paradigm.Methods: The study assessed the effects of an overnight hypothalamus-pituitary-adrenal (HPA) axis stimulation with metyrapone (MET) on baseline ANS activity through linear and non-linear heart rate variability (HRV) measures in the morning of two continuous days in a group of 14 physically healthy, antidepressant-free patients with clinical, non-psychotic MDD, to investigate differences in autonomic reactivity with respect to prior MDD history.Results: The main findings of this study include statistically significant time x group interactions with respect to several HRV measures, suggesting substantial differences on autonomic reactivity between patients with and without depression history. Hereby, recurrent-episode MDD patients showed lower vagal activity, while first-episode MDD patients increased PNS activity after HPA axis stimulation.Conclusions: These findings indicate that HPA axis stimulation in MDD patients leads to inverse vagal response according to MDD history. We suggest that chronic stress system overactivation, as found in MDD, might lead to a progressive inversion of the original stress response through HPA axis and ANS divergence over the course of a recurrent illness. HRV could, thus, represent a significant biomarker in MDD with temporal sensitivity.

BACKGROUND: . High-quality comprehensive data on short-/long-term physical/mental health effects of the COVID-19 pandemic are needed. METHODS: . The Collaborative Outcomes study on Health and Functioning during Infection Times (COH-FIT) is an international, multi-language (n=30) project involving >230 investigators from 49 countries/territories/regions, endorsed by national/international professional associations. COH-FIT is a multi-wave, on-line anonymous, cross-sectional survey [wave 1: 04/2020 until the end of the pandemic, 12 months waves 2/3 starting 6/24 months threreafter] for adults, adolescents (14-17), and children (6-13), utilizing non-probability/snowball and representative sampling. COH-FIT aims to identify non-modifiable/modifiable risk factors/treatment targets to inform prevention/intervention programs to improve social/health outcomes in the general population/vulnerable subgrous during/after COVID-19. In adults, co-primary outcomes are change from pre-COVID-19 to intra-COVID-19 in well-being (WHO-5) and a composite psychopathology P-Score. Key secondary outcomes are a P-extended score, global mental and physical health. Secondary outcomes include health-service utilization/functioning, treatment adherence, functioning, symptoms/behaviors/emotions, substance use, violence, among others. RESULTS: . Starting 04/26/2020, up to 14/07/2021 >151,000 people from 155 countries/territories/regions and six continents have participated. Representative samples of ≥1,000 adults have been collected in 15 countries. Overall, 43.0% had prior physical disorders, 16.3% had prior mental disorders, 26.5% were health care workers, 8.2% were aged ≥65 years, 19.3% were exposed to someone infected with COVID-19, 76.1% had been in quarantine, and 2.1% had been COVID 19-positive. LIMITATIONS: . Cross-sectional survey, preponderance of non-representative participants. CONCLUSIONS: . Results from COH-FIT will comprehensively quantify the impact of COVID-19, seeking to identify high-risk groups in need for acute and long-term intervention, and inform evidence-based health policies/strategies during this/future pandemics. ispartof: JOURNAL OF AFFECTIVE DISORDERS vol:299 pages:393-407 ispartof: location:Netherlands status: published

BACKGROUND: The COVID-19 pandemic has altered daily routines and family functioning, led to closing schools, and dramatically limited social interactions worldwide. Measuring its impact on mental health of vulnerable children and adolescents is crucial. METHODS: The Collaborative Outcomes study on Health and Functioning during Infection Times (COH-FIT - www.coh-fit.com) is an on-line anonymous survey, available in 30 languages, involving >230 investigators from 49 countries supported by national/international professional associations. COH-FIT has thee waves (until the pandemic is declared over by the WHO, and 6-18 months plus 24-36 months after its end). In addition to adults, COH-FIT also includes adolescents (age 14-17 years), and children (age 6-13 years), recruited via non-probability/snowball and representative sampling and assessed via self-rating and parental rating. Non-modifiable/modifiable risk factors/treatment targets to inform prevention/intervention programs to promote health and prevent mental and physical illness in children and adolescents will be generated by COH-FIT. Co-primary outcomes are changes in well-being (WHO-5) and a composite psychopathology P-Score. Multiple behavioral, family, coping strategy and service utilization factors are also assessed, including functioning and quality of life. RESULTS: Up to June 2021, over 13,000 children and adolescents from 59 countries have participated in the COH-FIT project, with representative samples from eleven countries. LIMITATIONS: Cross-sectional and anonymous design. CONCLUSIONS: Evidence generated by COH-FIT will provide an international estimate of the COVID-19 effect on children's, adolescents' and families', mental and physical health, well-being, functioning and quality of life, informing the formulation of present and future evidence-based interventions and policies to minimize adverse effects of the present and future pandemics on youth. ispartof: JOURNAL OF AFFECTIVE DISORDERS vol:299 pages:367-376 ispartof: location:Netherlands status: published

Multiple neurobiological pathways have been implicated in the pathobiology of major depressive disorder (MDD). The identification of reliable biological substrates across the entire MDD spectrum, however, is hampered by a vast heterogeneity in the clinical presentation, presumably as a consequence of heterogeneous pathobiology. One way to overcome this limitation could be to explore disease subtypes based on biological similarity such as "inflammatory depression". As such a subtype may be particularly enriched in depressed patients with an underlying inflammatory condition, multiple sclerosis (MS) could provide an informative disease context for this approach. Few studies have explored immune markers of MS-associated depression and replications are missing. To address this, we analyzed data from two independent case-control studies on immune signatures of MS-associated depression, conducted at two different academic MS centers (overall sample size of n = 132). Using a stepwise data-driven approach, we identified CD4

Background: Acute and chronic stress can lead to a dysregulation of the immune response. Growing evidence suggests peripheral immune dysregulation and low-grade systemic inflammation in posttraumatic stress disorder (PTSD), with numerous reports of elevated plasma interleukin-6 (IL-6) levels. However, only a few studies have assessed IL-6 levels in the cerebrospinal fluid (CSF). Most of those have used single time-point measurements, and thus cannot take circadian level variability and CSF-plasma IL-6 correlations into account.Methods: This study used time-matched, sequential 24-h plasma and CSF measurements to investigate the effects of combat stress and PTSD on physiologic levels and biorhythmicity of IL-6 in 35 male study volunteers, divided in 3 groups: (PTSD = 12, combat controls, CC = 12, and non-deployed healthy controls, HC = 11).Results: Our findings show no differences in diurnal mean concentrations of plasma and CSF IL-6 across the three comparison groups. However, a significantly blunted circadian rhythm of plasma IL-6 across 24 h was observed in all combat-zone deployed participants, with or without PTSD, in comparison to HC. CSF IL-6 rhythmicity was unaffected by combat deployment or PTSD.Conclusions: Although no significant group differences in mean IL-6 concentration in either CSF or plasma over a 24-h timeframe was observed, we provide first evidence for a disrupted peripheral IL-6 circadian rhythm as a sequel of combat deployment, with this disruption occurring in both PTSD and CC groups. The plasma IL-6 circadian blunting remains to be replicated and its cause elucidated in future research.

Traumatic stress may chronically affect master homeostatic systems at the crossroads of peripheral and central susceptibility pathways and lead to the biological embedment of trauma-related allostatic trajectories through neurobiological alterations even decades later. Lately, there has been an exponential knowledge growth concerning the effect of traumatic stress on oxidative components and redox-state homeostasis. This extensive review encompasses a detailed description of the oxidative cascade components along with their physiological and pathophysiological functions and a systematic presentation of both preclinical and clinical, genetic and epigenetic human findings on trauma-related oxidative stress (OXS), followed by a substantial synthesis of the involved oxidative cascades into specific and functional, trauma-related pathways. The bulk of the evidence suggests an imbalance of pro-/anti-oxidative mechanisms under conditions of traumatic stress, respectively leading to a systemic oxidative dysregulation accompanied by toxic oxidation byproducts. Yet, there is substantial heterogeneity in findings probably relative to confounding, trauma-related parameters, as well as to the equivocal directionality of not only the involved oxidative mechanisms but other homeostatic ones. Accordingly, we also discuss the trauma-related OXS findings within the broader spectrum of systemic interactions with other major influencing systems, such as inflammation, the hypothalamic-pituitary-adrenal axis, and the circadian system. We intend to demonstrate the inherent complexity of all the systems involved, but also put forth associated caveats in the implementation and interpretation of OXS findings in trauma-related research and promote their comprehension within a broader context.

Stress is defined as a state of threatened homeodynamic balance by a wide range of intrinsic or extrinsic, real or perceived challenges or stimuli, defined as stressors. To preserve this optimal homeodynamic state within a physiologic range, organisms have developed a highly sophisticated system, the stress system, which serves self-regulation and adaptability of the organism by energy redirection according to the current needs. Repeated, ephemeral, and motivating stress states lead to adaptive responses and response habituations, being fairly beneficial; in contrast, inadequate, aversive, excessive, or prolonged stress may surpass the regulatory capacity and adjustive resources of the organism and produce maladaptive responses and a chronically altered homeodynamic state associated with compromised mental and physical health and life expectancy. Neuroendocrine responses to stress depend on developmental timing, duration, time of day and nature of stressors leading to a vulnerable phenotype with disrupted stress reactivity (i.e., hyper- or hypoactivation of the stress system), impaired glucocorticoid signaling, and accumulated cacostatic load with cumulatively elevated long-term risk of mental and physical morbidity. This article offers a brief overview on the organization and physiology of the human stress system and its (re)activity, refreshes the plethora of somatic effects of acute and chronic stress and discusses a conceptual model of acute and chronic stress pathophysiology as a continuum in chronic disease development.

As of the end of 2020, the COVID-19 pandemic has led to over 82 million verified infections and almost 1.8 million COVID-19-related deaths worldwide,1 resulting to an unprecedented public health response around the globe. The COVID-19 pandemic, together with the applied multi-level restrictive measures, has generated a unique combination of an unpredictable and stressful biomedical and socioeconomic environment (i.e., syndemic),2 introducing real-life threat, involuntary and drastic every-day life-style changes with uncertain financial and future prospects, alongside with minimized coping and stress management possibilities.3 This combination of so many different and vital stressors may lead to acute as well as long-term, direct, indirect and even transgenerational unfavourable effects on physical and mental health and functioning, which might even represent the most precarious and still unpredictable public-health-related part of the pandemic.4 Thereby, specific population groups could be at particular risk of poor health outcomes in relation to applied public health measures.4, 5 However, not every individual will experience the same level of negative impact on health and well-being during the pandemic, as several additional national, socioeconomic, environmental, behavioural, emotional and cognitive factors can moderate individual resilience and coping.6 Pandemic-related research should, thus, assess as many multidimensional risk and protective factors as possible in a longitudinal, large-scale and multi-national manner, enabling a profound and comprehensive understanding of the complex health and societal impact of the pandemic worldwide.7 Nevertheless, to date, most research findings are cross-sectional, report on small and non- representative samples from individual countries, or on specific population groups (e.g., health care workers, students, clinical populations) and usually assess only a very restricted set of outcomes and time-points. Thereby, only few studies assess coping strategies, medical history or detailed socioeconomic, demographic and environmental data. In addition, most studies leave behind linguistic differences, being available in one or at best two different languages. Such investigations of small outcome subsets within a narrow framework preclude a broader and clear understanding of the multifaceted pandemic impact on the general population and specific subgroups. Acknowledging these gaps in the existing literature, large- scale, collaborative research prospectively collecting and monitoring a broad range of real- time, multi-dimensional health-related, societal and behavioural outcome data from countries across the globe is currently explicitly needed. The Collaborative Outcomes study on Health and Functioning during Infection Times (COH- FIT) envisions to fill this gap. Based on an easy-to-access webpage (www.coh-fit.com), COH- FIT is the currently largest-scale known international collaborative study of over 200 researchers around the globe, prospectively collecting the biggest set of multi-dimensional and multi-disciplinary data from 150 high, middle, and low-income countries in over 30 languages and in three different age groups (adults, adolescents, children) of the general population, focusing also on relevant at-risk subgroups. Albeit being a cross-sectional anonymous survey on an individual level, it is a longitudinal study on a population level, as data are collected continuously since April 2020 and until the WHO declares the end of the pandemic. In addition to snowball recruitment, this project also collects information from nationally representative samples. Furthermore, COH-FIT is the first study of this scale investigating pandemic effects on health and functioning measures between family members, while it also specifically assesses a large list of behavioral and coping factors (e.g., screen time, social media usage, physical activity, social interaction, religious practices, etc.) on outcomes of interest. COH-FIT also monitors changes in public health restrictive measures to enhance data harmonization across nations and time, and to better investigate their impact on physical and mental health, while it also collects information on changes in healthcare systems functioning. The COH-FIT project was worldwide first initiated in Greece after the ethics committee approval of the School of Medicine of the Aristotle University of Thessaloniki and is officially supported by the Hellenic Psychiatric Association, European Psychiatric Association, World Association of Social Psychiatry, ECNP Network on the Prevention of Mental Disorders and Mental Health Promotion, among many other national and international scientific associations. To date, COH-FIT has already collected >115,000 participations worldwide (>8,000 in Greece), but more participants are still needed, both during the second and third wave of the pandemic, as in the future, after the pandemic has ended. Currently, the COH-FIT survey actively collects the largest sample on multifactorial data on the impact of the COVD-19 pandemic on health and functioning not only in Greece, but around the globe. The elaborated design of COH-FIT and similar studies may allow a better identification of key parameters and population groups at increased risk during the pandemic, as well as potential targets for acute and long-term prevention or intervention strategies in the current as in possible future pandemics. A profound understanding of the health and societal impact of the pandemic could facilitate an optimized governmental, social and individual health preparedness during infection times8 and the bridging of individuals’, societal and systemic needs and actions through multi-level guideline development with the aim to improve mental health outcomes globally.

Childhood trauma (CT) refers to severe early life adversities, especially experiences of parental abuse and neglect. Patients with schizophrenia spectrum psychosis (SSP) report higher CT rates than the general population. As CT assessment in SSP samples has been mainly conducted retrospectively through adult recollections of childhood adverse events, reservations about the reliability and validity of these reports have arisen. We sought to explore the short-term reliability of retrospective CT reports in sixty-three patients with SSP, by assessing the concurrent validity and test-retest reliability of the data. Two CT self-report measures, the Childhood Experience of Care and Abuse Questionnaire (CECA.Q) and the Parental Bonding Instrument (PBI) were employed for this task. High concurrent validity was detected between CECA.Q antipathy scales and PBI care and overprotection scales; and between CECA.Q neglect scales and PBI care scales. High test-retest reliability was confirmed for all CECA.Q and PBI scales. Our findings indicate that retrospective CT self-report measures are a reliable means of assessing early life adversities in SSP. However, further provisions should be taken to increase the reliability of retrospective reports, especially corroboration of the events through other sources and removal of latent confounders, such as psychopathology, memory fallacies and social desirability biases.

The human circadian system creates and maintains cellular and systemic rhythmicity essential for the temporal organization of physiological processes promoting homeostasis and environmental adaptation. Sleep disruption and loss of circadian rhythmicity fundamentally affects master homeostasic regulating systems at the crossroads of peripheral and central susceptibility pathways, similar to acute or chronic stress and, thus, may play a central role in the development of stress-related disorders. Direct and indirect human and animal PTSD research accordingly suggests circadian-system-linked sleep, neuroendocrine, immune, metabolic and autonomic dysregulation, linking circadian misalignment to PTSD pathophysiology. Additionally, there is evidence that sleep and circadian disruption may represent a vital pre-existing risk factor in the prediction of PTSD development, while sleep-related symptoms are among the most prominent in trauma-associated disorders. These facts may represent a need for a shift towards a more chronobiological understanding of traumatic sequel and could support better prevention, evaluation and treatment of sleep and circadian disruption as first steps in PTSD management. In this special issue, we highlight and review recent advances from human sleep and chronobiological research that enhances our understanding of the development and maintenance of trauma-related disorders., HIGHLIGHTS Sleep and circadian disruption may be crucially involved in the development and maintenance of traumatic-stress-related disorders.There is a need for a chronobiological shift towards better evaluation, understanding and treatment of traumatic stress sequel.

Background: Humans have an evolutionary need for a well-preserved internal ‘clock’, adjusted to the 24-hour rotation period of our planet. This intrinsic circadian timing system enables the temporal organization of numerous physiologic processes, from gene expression to behaviour. The human circadian system is tightly and bidirectionally interconnected to the human stress system, as both systems regulate each other’s activity along the anticipated diurnal challenges. The understanding of the temporal relationship between stressors and stress responses is critical in the molecular pathophysiology of stress-and trauma-related diseases, such as posttraumatic stress disorder (PTSD). Objectives/Methods: In this narrative review, we present the functional components of the stress and circadian system and their multilevel interactions and discuss how traumatic stress can affect the harmonious interplay between the two systems. Results: Circadian dysregulation after trauma exposure (posttraumatic chronodisruption) may represent a core feature of trauma-related disorders mediating enduring neurobiological correlates of traumatic stress through a loss of the temporal order at different organizational levels. Posttraumatic chronodisruption may, thus, affect fundamental properties of neuroendocrine, immune and autonomic systems, leading to a breakdown of biobehavioral adaptive mechanisms with increased stress sensitivity and vulnerability. Given that many traumatic events occur in the late evening or night hours, we also describe how the time of day of trauma exposure can differentially affect the stress system and, finally, discuss potential chronotherapeutic interventions. Conclusion: Understanding the stress-related mechanisms susceptible to chronodisruption and their role in PTSD could deliver new insights into stress pathophysiology, provide better psychochronobiological treatment alternatives and enhance preventive strategies in stress-exposed populations., HIGHLIGHTS • The human circadian and stress system are both essential for biobehavioural regulation with numerous reciprocal interaction. • Posttraumatic chronodisruption (i.e., circadian dysregulation after trauma) represents a core feature of PTSD, mediating neurobiological correlates of trauma through multilevel temporal order loss.

Background Major depressive disorder (MDD) constitutes the leading cause of disability worldwide. Although efficacious antidepressant pharmacotherapies exist for MDD, only about 40-60% of the patients respond to initial treatment. However, there is still a lack of robustly established and applicable biomarkers for antidepressant response in everyday clinical practice. Objective This study targets the assessment of the vasopressin (AVP) surrogate marker Copeptin (CoP), as a potential peripheral hypothalamic-level biomarker of antidepressant treatment response in MDD. Methods We measured baseline and dynamic levels of plasma CoP along with plasma ACTH and cortisol (CORT) in drug-naive outpatients with MDD before and after overnight manipulation of the hypothalamic-pituitary-adrenal (HPA) axis [i.e., stimulation (metyrapone) and suppression (dexamethasone)] on three consecutive days and their association with treatment response to 4 weeks of escitalopram treatment. Results Our findings suggest significantly higher baseline and post-metyrapone plasma CoP levels in future non-responders, a statistically significant invert association between baseline CoP levels and probability of treatment response and a potential baseline plasma CoP cut-off level of above 2.9 pmol/L for future non-response screening. Baseline and dynamic plasma ACTH and CORT levels showed no association with treatment response. Conclusions This pilot study provide first evidence in humans that CoP may represent a novel, clinically easily applicable, endocrine biomarker of antidepressant response, based on a single-measurement, cut-off level. These findings, underline the role of the vasopressinergic system in the pathophysiology of MDD and may represent a significant new tool in the clinical and biological phenotyping of MDD enhancing individual-tailored therapies.

Traumatic stress exposure during critical periods of development may have essential and long-lasting effects on the physical and mental health of individuals. Two thirds of youth are exposed to potentially traumatic experiences by the age of 17, and approximately 5% of adolescents meet lifetime criteria for posttraumatic stress disorder (PTSD). The role of the stress system is the maintenance of homeostasis in the presence of real/perceived and acute/chronic stressors. Early-life stress (ELS) has an impact on neuronal brain networks involved in stress reactions, and could exert a programming effect on glucocorticoid signaling. Studies on pediatric PTSD reveal diverse neuroendocrine responses to adverse events and related long-term neuroendocrine and epigenetic alterations. Neuroendocrine, neuroimaging, and genetic studies in children with PTSD and ELS experiences are crucial in understanding risk and resilience factors, and also the natural history of PTSD.

Early life stressors display a high universal prevalence and constitute a major public health problem. Prolonged psychoneurobiological alterations as sequelae of early life stress (ELS) could represent a developmental risk factor and mediate risk for disease, leading to higher physical and mental morbidity rates in later life. ELS could exert a programming effect on sensitive neuronal brain networks related to the stress response during critical periods of development and thus lead to enduring hyper- or hypo-activation of the stress system and altered glucocorticoid signaling. In addition, alterations in emotional and autonomic reactivity, circadian rhythm disruption, functional and structural changes in the brain, as well as immune and metabolic dysregulation have been lately identified as important risk factors for a chronically impaired homeostatic balance after ELS. Furthermore, human genetic background and epigenetic modifications through stress-related gene expression could interact with these alterations and explain inter-individual variation in vulnerability or resilience to stress. This narrative review presents relevant evidence from mainly human research on the ten most acknowledged neurobiological allostatic pathways exerting enduring adverse effects of ELS even decades later (hypothalamic-pituitary-adrenal axis, autonomic nervous system, immune system and inflammation, oxidative stress, cardiovascular system, gut microbiome, sleep and circadian system, genetics, epigenetics, structural, and functional brain correlates). Although most findings back a causal relation between ELS and psychobiological maladjustment in later life, the precise developmental trajectories and their temporal coincidence has not been elucidated as yet. Future studies should prospectively investigate putative mediators and their temporal sequence, while considering the potentially delayed time-frame for their phenotypical expression. Better screening strategies for ELS are needed for a better individual prevention and treatment.

Childhood trauma (CT) is a comprehensive concept encompassing experiences of sexual, physical, and emotional abuse, and neglect during childhood and adolescence. Patients with schizophrenia-spectrum psychosis (SSP) display higher rates of CT than healthy controls. Among the potential mediators of this association, insecure attachment has gained attention and empirical validation. The present study aimed to extend existing knowledge on this field by exploring the role of the two attachment dimensions, attachment anxiety and attachment avoidance, in the CT-SSP association. A clinical sample of 63 SSP inpatients was compared to a healthy control group on CT and attachment style measures. Correlations between CT, attachment dimensions and psychopathology were sought. Mediation analyses were also performed to examine whether attachment anxiety and/or attachment avoidance mediated the CT-SSP association. Patients displayed higher rates of CT and insecure attachment than controls. Attachment anxiety and severity of Mother Antipathy were linked to severity of hallucinations. Attachment anxiety was recognized as the sole mediator of the CT-SSP association. Our findings suggest that individuals with severe CT and increased attachment anxiety represent a risk population warranting early clinical attention, regular monitoring and tailored therapeutic interventions aimed at reducing the psychological impact of trauma.

Background: The hypothalamic-pituitary-adrenal axis (I-IPA axis) and the autonomic nervous system (ANS) are considered to play the most crucial role in the pathophysiology of stress responsiveness and are increasingly studied together. However, only few studies have simultaneously assessed HPA axis and ANS activity to investigate their direct interaction in pathophysiology, while no study so far has assessed the dynamic interplay between the two systems in healthy subjects through endocrine challenges.Methods: The present study assessed the direct effects of overnight pharmacoendocrine HPA axis challenges with dexamethasone (suppression) and metyrapone (stimulation) on ANS activity at rest as determined by linear and nonlinear measures of heart rate variability (HRV) in 39 young healthy individuals.Results: Findings indicated significant effects of metyrapone, but not dexamethasone on autonomic activity at rest based on HRV measures. HRV after metyrapone was overall significantly reduced in comparison to baseline or post-dexamethasone conditions, while the combined metyrapone-related reduction of HRV measures RMSSD, NN50(%) and HF(%) with concomitant increase of the unifractal scaling coefficient alpha(fast), value jointly indicated a specifically diminished vagal activity.Conclusions: We provide first data that HPA axis stimulation (metyrapone) is associated with reduced vagal tone, while HPA axis suppression (dexamethasone) has no effect on autonomic modulation of heart function. Our results support a vital role of the parasympathetic nervous system in the interplay between ANS and HPA axis and, thus, in the modulation of stress-related cardiovascular responsiveness and the susceptibility to stress related disorders.

Experience of early life stress (ELS) and trauma is highly prevalent in the general population and has a high public health impact, as it can trigger a health-related risk cascade and lead to impaired homeostatic balance and elevated cacostatic load even decades later. The prolonged neuropsychobiological impact of ELS can, thus, be conceptualized as a common developmental risk factor for disease associated with increased physical and mental morbidity in later life. ELS during critical periods of brain development with elevated neuroplasticity could exert a programming effect on particular neuronal networks related to the stress response and lead to enduring neuroendocrine alterations, i.e., hyper- or hypoactivation of the stress system, associated with adult hypothalamic-pituitary-adrenal axis and glucocorticoid signaling dysregulation. This paper reviews the pathophysiology of the human stress response and provides evidence from human research on the most acknowledged stress axis-related neuroendocrine pathways exerting the enduring adverse effects of ELS and mediating the cumulative long-term risk of disease vulnerability in adulthood.

Depression und koronare Herzerkrankung (KHK) sind fuhrende Ursachen der globalen Krankheitslast und weisen eine hohe Komorbiditat auf. Zudem stellt die Depression einen unabhangigen Risikofaktor fur einen ungunstigeren Verlauf der KHK dar. Umgekehrt kann eine erfolgreiche Depressionsbehandlung zur Reduktion des kardialen Risikos fuhren. Aktuell stehen unterschiedliche Therapieoptionen zur Behandlung der Depression bei Patienten mit komorbider KHK zur Verfugung, die stufenweise oder kombiniert Anwendung finden. Eine besondere Bedeutung kommt dabei dem Selbstmanagement, der Psychotherapie, der Pharmakotherapie und neuen Versorgungsmodellen zu. Dieser Artikel bietet eine Ubersicht zur Epidemiologie und Pathophysiologie der Depression bei Patienten mit KHK sowie zur Effektivitat und Sicherheit verschiedener Therapieoptionen.

Dysfunktionale Denkmuster spielen vermutlich eine wichtige Rolle bei der Entstehung und Aufrechterhaltung der Borderline-Persönlichkeitsstörung. Daher erscheint es bedeutsam, derartige (meta-)kognitive Verzerrungen stärker in den Fokus empirischer Untersuchungen zu rücken und vermehrt in Therapiepläne zu integrieren. Ausgehend von bisherigen Befunden der kognitiven Grundlagenforschung wurde von unserer Arbeitsgruppe das «Metakognitive Training – Borderline» (B-MKT) entwickelt. Dieses niedrigschwellige, kognitiv-verhaltenstherapeutisch ausgerichtete Gruppenangebot soll den Patienten dysfunktionale Denkmuster bewusst machen und helfen, diese wirkungsvoll zu verändern. Das B-MKT versteht sich als add-on Therapiebaustein zur stationären oder ambulanten Standardbehandlung. Primäres Ziel ist die Reduktion von dysfunktionalen Denkverzerrungen.

Pre-existing knowledge, a 'schema', facilitates the encoding, consolidation, and retrieval of schema-relevant information. Such schema-based memory is key to every form of education and provides intriguing insights into the integration of new information and prior knowledge. Stress is known to have a critical impact on memory processes, mainly through the action of glucocorticoids and catecholamines. However, whether stress and these major stress mediators affect schema-based learning is completely unknown. To address this question, we performed two experiments, in which participants acquired a schema on day 1 and learned schema-related as well as schema-unrelated information on day 2. In the first experiment, participants underwent a stress or control manipulation either immediately or about 25 min before schema-based memory testing. The second experiment tested whether glucocorticoid and/or noradrenergic activation is sufficient to modulate schema-based memory. To this end, participants received orally a placebo, hydrocortisone, the α2-adrenoceptor-antagonist yohimbine, leading to increased noradrenergic stimulation, or both drugs, before completing the schema-based memory test. Our data indicate that stress, irrespective of the exact timing of the stress exposure, impaired schema-based learning, while leaving learning of schema-unrelated information intact. A very similar effect was obtained after hydrocortisone, but not yohimbine, administration. These data show that stress disrupts participants' ability to benefit from prior knowledge during learning and that glucocorticoid activation is sufficient to produce this effect. Our findings provide novel insights into the impact of stress and stress hormones on the dynamics of human memory and have important practical implications, specifically for educational contexts.

Loss of circadian rhythmicity fundamentally affects the neuroendocrine, immune and autonomic system, similar to chronic stress and may play a central role in the development of stress-related disorders. Recent articles have focused on the role of sleep and circadian disruption in the pathophysiology of posttraumatic stress disorder (PTSD), suggesting that chronodisruption plays a causal role in PTSD development. Direct and indirect human and animal PTSD research suggests circadian-system-linked neuroendocrine, immune, metabolic and autonomic dysregulation, linking circadian misalignment to PTSD pathophysiology. Recent experimental findings also support a specific role of the fundamental synchronizing pineal hormone melatonin in mechanisms of sleep, cognition and memory, metabolism, pain, neuroimmunomodulation, stress endocrinology and physiology, circadian gene expression, oxidative stress and epigenetics, all processes affected in PTSD. In the current paper, we review available literature underpinning a potentially beneficiary role of an add-on melatonergic treatment in PTSD pathophysiology and PTSD-related symptoms. The literature is presented as a narrative review, providing an overview on the most important and clinically relevant publications. We conclude that adjuvant melatonergic treatment could provide a potentially promising treatment strategy in the management of PTSD and especially PTSD-related syndromes and comorbidities. Rigorous pre-clinical and clinical studies are needed to validate this hypothesis.

Heart rate variability (HRV), determined by different methods from the fluctuation of heart rate (HR), has been used in many studies as a powerful index of autonomic function and indicator of cardiac risk. Here, we review how HRV measures in different domains such as time, frequency, and nonlinear domains have been successfully used to identify increased cardiac risk in PTSD patients. PTSD patients show high cardiac comorbidity that may have emerged for various reasons but is predominantly attributed to altered autonomic control. The deranged fear or “stress” system is implicated in affective and autonomic system dysfunctions. The underlying neurocircuitry and molecular key players of autonomic dysfunction in PTSD are still poorly understood. A malfunctioning cortical control of the downstream defense system is hypothesized to be causal for the blunted tonic vagal control and/or increased sympathetic activity that generally leads to increased HR, reduced HRV, and blunted diurnal/circadian changes compared to the healthy state. Altered serotonergic neurotransmission is likely involved in the reduced vagal function. Nonlinear approaches in combination with animal models are required to provide a better mechanistic understanding of the neural and molecular mechanisms underlying the healthy and the malfunctioning brain-heart interaction in PTSD. List of Abbreviations ANS Autonomic nervous system bpm Beats per minute DFA Detrended fluctuation analysis HR Heart rate HRV Heart rate variability PNS Parasympathetic nervous system PTSD Post-traumatic stress disorder RSA Respiratory sinus arrhythmia SNS Sympathetic nervous system SSRI Selective serotonin reuptake inhibitor *Email: oliver.stiedl@cncr.vu.nl *Email: r.o.stiedl@vu.nl Comprehensive Guide to Post-Traumatic Stress Disorder DOI 10.1007/978-3-319-08613-2_30-1 # Springer International Publishing Switzerland 2015

Introduction: This evaluation is part of a Twinning Project between Cyprus and Germany, aimed at evaluating the governmental drug services in Cyprus and promoting the improvement and introduction of new drug treatment services, in order to assist the new Member State in the implementation and harmonization with the European Community's legislation.Methods: A field investigation studied parameters as population in need, treatment demand and coverage, as well as high-risk patterns and their trend over the past years.Results: The main findings were a high level of problematic drug use, mainly high-risk intravenous heroin and cocaine use, and an increase treatment demand for women, adolescents and migrants. Expert interviews named gaps in treatment options, including a previous lack of maintenance treatment, insufficient harm reduction measures and inadequate treatment concepts to meet specific needs of problematic drug users.Discussion: Recommendations for improvement can be integrated into present services....

Glaucoma is a frequent ophthalmologic condition leading to chronic progressive optic neuropathy, which can result in visual impairment and blindness. In addition, glaucoma is associated with a dysregulation of circadian rhythms, as well as with a high incidence of sleep disorders, depression, and anxiety. However, because of their high comorbidity in older age, these conditions have not received much scientific attention and are often undertreated. In the current paper, we review the available literature on the role of melatonergic mechanisms in glaucoma, regulation of circadian rhythms, and depression. The literature is presented as a narrative review, providing an overview on the most important and clinically relevant publications. Recently, there has been evidence for a progressive loss of intrinsically photosensitive retinal ganglion cells (ipRGC) because of oxidative stress in glaucoma. As ipRGC are responsible for the photic transduction to the circadian system and subsequent melatonin secretion, and melatonin is involved in the pathophysiology of circadian desynchronization, sleep disorder, and depression, an impairment of photo-dependent melatonergic signaling may be a common pathway connecting glaucoma with these comorbidities. This fact, as well as the proven retinal neuroprotective role of melatonin, suggests that melatonergic drugs provide a potentially promising treatment strategy supplementing the management of intraocular pressure by pharmacological and surgical measures. Additionally, multidisciplinary treatment focusing on depression and normalization of circadian rhythms might be beneficial for glaucoma patients. Furthermore, glaucoma might be a useful model for studying the pathophysiological interactions between the melatonergic, circadian, and mood systems.

Although acupuncture treatment is increasingly in demand among psychiatric patients, to date no studies have investigated the effectiveness of auricular acupuncture (AA) in treating anxiety disorders or major depressive disorder. Thus, this study aimed to compare the effectiveness of AA versus progressive muscle relaxation (PMR), a standardized and accepted relaxation method. We examined 162 patients with a primary diagnosis of anxiety disorder or major depressive disorder, and each patient chose between treatment with AA, executed according to the National Acupuncture Detoxification Association protocol, and treatment with PMR. Each group had treatments twice a week for 4 weeks. Before and after treatment, each participant rated four items on a visual analog scale: anxiety, tension, anger/aggression, and mood. Statistical analyses were performed with the original visual analog scale scores and the Change-Intensity Index, an appropriate indicator of the difference between two values of a variable. Our results show that treatment with AA significantly decreased tension, anxiety, and anger/aggression throughout the 4 weeks, but did not elevate mood. Between AA and PMR, no statistically significant differences were found at any time. Thus, we suggest that both AA and PMR may be useful, equally-effective additional interventions in the treatment of the above-mentioned disorders.

History of childhood trauma (CT) is highly prevalent and may lead to long-term consequences on physical and mental health. This study investigated the independent association of CT with symptoms of adult depression and posttraumatic stress disorder (PTSD), mental and physical health-related quality of life (HRQoL), as well as current tobacco consumption and alcohol abuse in a large homogenous cohort of 1254 never-deployed, young male Marines enrolled in the Marine Resiliency Study. Independent effects of CT history, number and type of CT on outcomes were analyzed using hierarchical multivariate logistic regression models. Our results suggested dose-dependent negative effect of an increasing number of trauma types of CT on depression, PTSD and HRQoL. Experience of single CT type demonstrated overall weak effects, while history of multiple CT types distinctively increased the likelihood of adult PTSD symptomology (OR: 3.1, 95% CI: 1.5e6.2), poor mental (OR: 2.3, 95% CI: 1.7e3.1) and physical HRQoL (OR: 1.4, 95% CI: 1.1e1.9). Risk for depression symptoms was similar for both single and multiple CT (OR: 2.2, 95% CI: 1.3e3.8 and OR: 2.1, 95% CI: 1.2e3.5 respectively). CT history had no effects on current tobacco use and alcohol abuse. Our study thus provides evidence for substantial additive effect of different CT types on adult mental and physical health with increasing levels of exposure. Published by Elsevier Ltd.

The development of acute and posttraumatic stress symptoms after a traumatic event is common and often leads to personal distress, functional impairment, and economic consequences in trauma victims and their loved ones. Hence, the prevention of acute and chronic posttraumatic stress is an important public health priority. This article aims to review the current evidence regarding immediate (within hours) and early (within days and weeks) psychological and behavioral interventions to prevent posttraumatic stress symptoms.Acute distress management, psychological debriefing and other immediate unspecific interventions within the first hours following a traumatic event have so far not demonstrated efficacy in preventing posttraumatic stress symptoms. So far, there are no randomized controlled trials (RCTs) that have examined immediate trauma-focused cognitive behavioral interventions. In contrast, some, but not many, studies have shown that cognitive behavioral interventions are efficacious if administered within days or weeks after a traumatic event. For other early interventions after trauma exposure, there is no, or only weak, evidence in support of their efficacy. However, conclusions are limited by the small numbers of trials examining immediate and early interventions.Today, there is no empirical evidence to support any immediate intervention within hours after the traumatic event to prevent posttraumatic stress symptoms. With regard to early interventions in the first days or weeks after trauma, literature is also sparse, but supports brief cognitive behavioral interventions as a first choice. There is an urgent need for RCTs to examine if behavioral interventions immediately following a traumatic event might be able to reduce the burden of acute and posttraumatic stress symptoms.

Vitamin D deficiency is common in patients with insufficient sunlight exposure and nutritional deficit in calcium and vitamin D. We present a patient with vitamin D deficiency, secondary hyperparathyroidism and resulting osteoporotic fractures caused or supported by psychosis-induced minimal sunlight exposure and nutritional deficits. To our knowledge, this is the first case where delusional ideas could have led to a vitamin D deficiency, secondary hyperparathyroidism and osteoporotic fractures. Similar clinical cases could be more often, but significantly underdiagnosed, among schizophrenia patients. An appropriate prevention by UV light exposure, food fortification and supplements is normally sufficient for patients at risk.